Method for efficiently synthesizing marbofloxacin key intermediate
The intermediate IV of mapofloxacin was prepared by using cheap tetrafluorobenzoyl chloride, N,N-dimethylaminoacrylate and formylmethylhydrazine for a one-pot two-step reaction, which solved the traditional method's medium and high cost and The problem of excessive reaction steps achieves a more economical and efficient production process.
Patent Information
- Application Number
- CN202411631886.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-15
- Publication Date
- 2025-02-25
AI Technical Summary
The traditional intermediate IV method for synthesizing mapofloxacin has the problem of using high-cost ethyl 2,3,4,5-tetrafluorobenzoylacetate, irritating acetic anhydride and excessively long reaction steps, which leads to unsuitable industrialization. Production.
Inexpensive tetrafluorobenzoyl chloride, N,N-dimethylaminoacrylate and formylmethylhydrazine were used as substrates to form Intermediate II through a one-pot two-step reaction, followed by hydrolysis and decomposition under dilute sulfuric acid conditions. Formoyl group, and finally substituted with methylpiperazine, the target intermediate IV was prepared.
This method avoids the use of high-cost ethyl 2,3,4,5-tetrafluorobenzoylacetate and irritating acetic anhydride, simplifies the reaction steps, reduces production costs, and increases yields, which are suitable for industrialization Production.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of veterinary drug synthesis, and specifically relates to the synthesis of a key intermediate of marbofloxacin, 6,8-difluoro-1-(methylamino)-7-(4-methylpiperazine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (intermediate IV). Background Art
[0002] The chemical formula of 6,8-difluoro-1-(methylamino)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Intermediate IV) is: C6H6F2N2O2.
[0003]
[0004] Marbofloxacin is a new type of fluoroquinolone antibiotic, belonging to the third generation of quinolone antibiotics. It was first developed by Roche in Switzerland and further developed by Vetoquinol in France. It was launched in the UK and France in 1995. The drug inhibits bacterial growth by inhibiting bacterial DNA transcriptase. It has antibacterial effects on Gram-negative bacteria, Gram-positive bacteria and mycoplasma. It has a wide range of antibacterial activity and very good kinetic characteristics. It has strong bactericidal power and is a new type of antibacterial drug for animals. Marbofloxacin can be well absorbed by oral and injection administration, and has low toxic side effects.
[0005] Among them, intermediate IV is the key intermediate for synthesizing marbofloxacin. Based on the cost calculation of marbofloxacin, it is found that the unit material cost of marbofloxacin is about 2000, of which the initial material (intermediate IV) accounts for about 85%, which seriously affects the subsequent industrial production.
[0006] Traditionally, the method for synthesizing intermediate IV mainly uses ethyl 2,3,4,5-tetrafluorobenzoyl acetate as the initial substrate, and can be prepared through four steps of reaction. However, this type of reaction has the following problems: ① the use of irritating acetic anhydride; ② the high cost of ethyl 2,3,4,5-tetrafluorobenzoyl acetate; ③ the reaction steps are too long, etc., which makes it unsuitable for industrial production.
[0007]
[0008] Taking ethyl 2,3,4,5-tetrafluorobenzoyl acetate as the initial substrate, through cost calculation, the unit material cost of marbofloxacin can be reduced to about 1000. Among them, ethyl 2,3,4,5-tetrafluorobenzoyl acetate accounts for about 50%. In order to further reduce the cost of production, a variety of methods for synthesizing ethyl 2,3,4,5-tetrafluorobenzoyl acetate have been developed. For example, using 2,3,4,5-tetrafluorobenzoic acid as the initial substrate, ethyl 2,3,4,5-tetrafluorobenzoyl acetate can be prepared after chlorination, condensation of diethyl malonate, and partial hydrolysis and decarboxylation. Although the unit cost can be further reduced, this process is too long and requires the use of Grignard reagents.
[0009] Summary of the invention
[0010] In order to solve the above technical problems, the present invention provides a method for synthesizing 6,8-difluoro-1-(methylamino)-7-(4-methylpiperazine-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (intermediate IV), a key intermediate of marbofloxacin, wherein cheap tetrafluorobenzoyl chloride, N,N-dimethylamino ethyl acrylate and formylmethyl hydrazine are used as substrates, and intermediate II is generated after a one-pot two-step reaction. Intermediate II is hydrolyzed and deformylated under dilute sulfuric acid conditions to prepare intermediate III. Intermediate III is subjected to a substitution reaction with methylpiperazine to prepare target intermediate IV. Compared with conventional methods, this process avoids the use of expensive ethyl 2,3,4,5-tetrafluorobenzoyl acetate, the use of irritating acetic anhydride, etc., and only needs to use cheap and readily available substrates, and the target intermediate can be prepared by simple temperature rise and fall and filtering operations. In summary, this strategy is simpler to operate, uses cheap and readily available substrates, and has a high yield.
[0011] The reaction formula is:
[0012]
[0013] Synthesis of intermediate I: tetrafluorobenzoyl chloride and ethyl N,N-dimethylaminoacrylate undergo a substitution reaction under triethylamine conditions to generate intermediate I; more specifically, tetrafluorobenzoyl chloride and triethylamine are dissolved in a solvent, and ethyl N,N-dimethylaminoacrylate is added dropwise to perform a substitution reaction to generate intermediate I;
[0014] Synthesis of intermediate II: Intermediate I is subjected to a hydroamination substitution reaction with formylmethylhydrazine to generate intermediate II.
[0015] The synthesis of intermediate II can also adopt a one-pot two-step reaction, directly using tetrafluorobenzoyl chloride, N,N-dimethylaminoethyl acrylate and formylmethylhydrazine as the initial materials, and preparing intermediate I without separation, and the one-pot method is prepared, and the specific steps are as follows:
[0016] 1) Tetrafluorobenzoyl chloride and N,N-dimethylamino ethyl acrylate are subjected to substitution reaction under triethylamine conditions to generate intermediate I (without separation);
[0017] 2) Intermediate I undergoes a hydroamination substitution reaction with formylmethylhydrazine to generate intermediate II.
[0018] In the substitution reaction of step 1), the molar ratio of tetrafluorobenzoyl chloride, ethyl N,N-dimethylaminoacrylate and triethylamine is 1.0:1.0-1.3:1.0-1.5, and more preferably the molar ratio of tetrafluorobenzoyl chloride, ethyl N,N-dimethylaminoacrylate and triethylamine is 1.0:1.0-1.1:1.2-1.4, and the reaction solvent is toluene.
[0019] Synthesis of intermediate III: Intermediate II is hydrolyzed and deformylated under dilute sulfuric acid conditions to obtain intermediate III.
[0020] Synthesis of intermediate IV: Intermediate III undergoes substitution reaction with methylpiperazine to obtain intermediate IV.
[0021] In the above-mentioned synthesis method of intermediate I, the molar ratio of tetrafluorobenzoyl chloride, N,N-dimethylaminoethyl acrylate and triethylamine is preferably 1.0:1.05:1.3.
[0022] In the above-mentioned synthesis method of intermediate I, the reaction solvent is toluene.
[0023] In the above-mentioned synthesis method of intermediate I, the dropping temperature is 35-40°C, the reaction temperature is 80-90°C, and the reaction time is 2-4h.
[0024] In the above-mentioned synthesis method of intermediate II, the molar ratio of intermediate I to formylmethylhydrazine is 1.0:1.0-1.3, preferably 1.0:1.1.
[0025] In the above-mentioned synthesis method of intermediate II, the reaction solvent is toluene.
[0026] In the above-mentioned synthesis method of intermediate II, the dropping temperature is 20-25° C., the reaction temperature is reflux, and the reaction time is 0.5-2 h.
[0027] In the above-mentioned synthesis method of intermediate II, the reaction further comprises a post-treatment step, wherein after the reaction is completed, the reaction is cooled, filtered, and dried to obtain intermediate II.
[0028] In the above-mentioned synthesis method of intermediate III, the molar ratio of intermediate II to sulfuric acid is 1.0:1.0-1.2.
[0029] In the above-mentioned synthesis method of intermediate III, the reaction solvent is water.
[0030] In the above-mentioned synthesis method of intermediate III, the reaction temperature is reflux and the reaction time is 7 to 10 hours.
[0031] In the above-mentioned synthesis method of intermediate III, the reaction further comprises a post-treatment step, wherein after the reaction is completed, the reaction is cooled, filtered, and dried to obtain intermediate III.
[0032] In the above-mentioned synthesis method of intermediate IV, the molar ratio of intermediate III to methylpiperazine is 1.0:1.0-1.1; more preferably, the molar ratio of intermediate III to methylpiperazine is 1.0:1.02-1.06.
[0033] In the above-mentioned synthesis method of intermediate IV, the reaction solvent is anhydrous ethanol.
[0034] In the above-mentioned synthesis method of intermediate IV, the reaction temperature is reflux and the reaction time is 6 to 8 hours.
[0035] In the above-mentioned synthesis method of intermediate IV, the reaction further comprises a post-treatment step, wherein after the reaction is completed, the reaction is cooled, filtered, and dried to obtain intermediate IV.
[0036] Beneficial effects:
[0037] Compared with the prior art, the present invention has the following advantages:
[0038] (1) Using cheaper tetrafluorobenzoyl chloride as the starting raw material avoids the use of ethyl 2,3,4,5-tetrafluorobenzoyl acetate, thereby further reducing the cost;
[0039] (2) The process of using N,N-dimethylamino ethyl acrylate to react with tetrafluorobenzoyl chloride to generate intermediate I has obvious advantages over the prior art: ① In the prior art, tetrafluorobenzoyl chloride needs to react with a Grignard reagent to prepare ethyl 2,3,4,5-tetrafluorobenzoyl acetate, which requires multiple steps such as deesterification, while the scheme of the present invention can directly synthesize the same intermediate I in one step. ② In the prior art, ethyl 2,3,4,5-tetrafluorobenzoyl acetate needs to react with triethyl orthoformate and acetic anhydride, and then react with formylmethylhydrazine. The scheme of the present invention can directly synthesize the same intermediate I in one step without the need for excessively high reaction temperatures and avoids the use of irritating acetic anhydride.
[0040] (3) The intermediate II is synthesized by a one-pot two-step method using cheap materials, which has obvious step economy, high yield, mild reaction conditions, etc., further reducing the material cost of marbofloxacin and making it more suitable for industrial production. DETAILED DESCRIPTION
[0041] The present invention will be further described below in conjunction with specific embodiments so that those skilled in the art can better understand the present invention, but the invention is not limited thereby.
[0042] The present invention uses cheap tetrafluorobenzoyl chloride, N,N-dimethylaminoethyl acrylate and formylmethylhydrazine as substrates, and generates intermediate II after a one-pot two-step reaction. Intermediate II is hydrolyzed and deformylated under dilute sulfuric acid conditions to prepare intermediate III. Intermediate III is subjected to a substitution reaction with methylpiperazine to prepare target intermediate IV. The synthetic route is shown in the following formula:
[0043]
[0044] Example 1 One-pot two-step method for preparing intermediate II
[0045]
[0046] Add 2.11kg (10mol) of tetrafluorobenzoyl chloride, 1.35kg (13mol) of triethylamine and 5L of toluene to a 20L reactor, replace with nitrogen three times, control the internal temperature of the material at 38°C, and slowly drop 1.5kg (10.5mol) of N,N-dimethylamino ethyl acrylate for 2h. After the addition, control the internal temperature of the material to 88°C, and keep warm for 2 hours (central control: residual rate of tetrafluorobenzoyl chloride ≤1.0%). After the reaction, add 0.81kg (11mol) of formylmethyl hydrazine and 1L of toluene to the dropping funnel, control the internal temperature of the material to 23°C, and slowly drop the prepared toluene solution of formylmethyl hydrazine into the reactor. After the drop, heat to reflux and reflux for 2 hours (central control: residual rate of intermediate I ≤1.0%). After the reaction, reduce the internal temperature of the material to -10°C, stir for 1 hour, and filter to dryness. The mixture was dried under reduced pressure at 60°C for 12 hours to obtain 2.98 kg of intermediate II, which was a light yellow solid with a purity of 98.8% and a yield of 89.9%.
[0047] Example 2 One-pot two-step method for preparing intermediate II
[0048]
[0049] Add 2.11kg (10mol) of tetrafluorobenzoyl chloride, 1.35kg (13mol) of triethylamine and 5L of toluene to a 20L reactor, replace with nitrogen three times, control the internal temperature of the material at 38°C, and slowly drop 1.5kg (10.5mol) of N, N-dimethylamino ethyl acrylate. After the addition, control the internal temperature of the material to 90°C, and keep warm for 2 hours (central control: residual rate of tetrafluorobenzoyl chloride ≤1.0%). After the reaction, add 0.81kg (11mol) of formylmethyl hydrazine and 1L of toluene to the dropping funnel, control the internal temperature of the material to 23°C, and slowly drop the prepared toluene solution of formylmethyl hydrazine into the reactor. After the drop, heat to reflux and reflux for 1.5 hours (central control: residual rate of intermediate I ≤1.0%). After the reaction, reduce the internal temperature of the material to -10°C, stir for 1 hour, and filter to dryness. The mixture was dried under reduced pressure at 60°C for 12 hours to obtain 2.95 kg of intermediate II, which was a light yellow solid with a purity of 98.7% and a yield of 90.8%.
[0050] Example 3 Preparation of Intermediate III
[0051]
[0052] Add 4.85kg (9.9mol) of 20% sulfuric acid to a 20L reactor, add 2.98kg (9.08mol) of intermediate II under stirring, reflux for 7 hours, and take samples for analysis (central control: residual rate of intermediate II ≤ 1.0%). After the reaction, cool to 2°C, stir for 2 hours, and filter. Add 1kg of tap water to rinse the filter cake, filter it to dryness, and dry it under reduced pressure at 60°C for 12 hours to obtain 2.27kg of intermediate III, which is a light yellow solid with a purity of 99.2% and a yield of 91.9%.
[0053] Example 4 Preparation of Intermediate III
[0054]
[0055] Add 4.85kg (9.9mol) of 20% sulfuric acid to a 20L reactor, add 2.98kg (9.08mol) of intermediate II under stirring, reflux for 8 hours, and take samples for analysis (central control: residual rate of intermediate II ≤ 1.0%). After the reaction, cool to 3°C, stir for 2 hours, and filter. Add 1kg of tap water to rinse the filter cake, filter to dryness, and dry under reduced pressure at 60°C for 12 hours to obtain 2.21kg of intermediate III, which is a light yellow solid with a purity of 99.2% and a yield of 89.5%.
[0056] Example 5 Synthesis of Intermediate IV
[0057]
[0058] In a 20L reactor, add 4L of anhydrous ethanol, 2.27kg (8.34mol) of intermediate III, and 0.87kg (8.69mol) of methylpiperazine, reflux for 6 hours, and take samples for testing (central control: residual rate of intermediate III ≤ 1.0%). After the reaction, cool to 4°C, stir for 2 hours, filter to dryness, dry under reduced pressure at 60°C for 12 hours, and dry the material to obtain 2.67kg of intermediate IV, which has a light yellow solid appearance, a purity of 99.6%, and a yield of 90.8%.
[0059] Example 6 Synthesis of Intermediate IV
[0060]
[0061] In a 20L reactor, add 4L of anhydrous ethanol, 2.27kg (8.34mol) of intermediate III, and 0.87kg (8.69mol) of methylpiperazine, reflux for 7 hours, and take samples for testing (central control: residual rate of intermediate III ≤ 1.0%). After the reaction, cool to 3°C, stir for 2 hours, filter to dryness, dry under reduced pressure at 60°C for 12 hours, and dry the material to obtain 2.70kg of intermediate IV, which has a light yellow solid appearance, a purity of 99.6%, and a yield of 91.8%.
[0062] The characterization data of the synthesized intermediate IV are as follows: Mp 217.3~217.6℃; 1 H NMR (CDCl3, 400MHz):δ H 2.39(s,3H,CH3),2.59~2.61(t,J=4.4Hz,4H,CH2),2.97~3.00(d,J=5.6Hz, 3H, CH3), 3.46~3.48 (t, J=4.4Hz, 4H, CH2), 5.84~5.90 (m, 1H, NH), 7.91~7.9 4(m,1H,ArH),8.77(s,1H,ArH),14.55(s,1H,COOH).(KBr):ν3228,2924,28 48,2807,1728,1627,1608,1555,1501,1452,1326,1242,1148,1079,932cm -1 .HRMS(ESI,m / z):Calcd for[C 16 H 17 F2N4O3] - [MH] - 351.1269, found 351.1269.
Claims
1. A method for efficiently synthesizing the key intermediate IV of Marbofloxacin, characterized in that: The method uses tetrafluorobenzoyl chloride, N,N-dimethylaminoethyl acrylate and formylmethylhydrazine as initial materials to prepare intermediate II; intermediate II is hydrolyzed and deformylated to obtain intermediate III, and intermediate III is subjected to substitution reaction with methylpiperazine to obtain intermediate IV; the synthesis route is shown in the following formula:
2. The method for efficiently synthesizing the key intermediate IV of Marbofloxacin according to claim 1, characterized in that: The synthesis of intermediate II comprises the following steps: 1) Dissolve tetrafluorobenzoyl chloride and triethylamine in a solvent, and dropwise add ethyl N,N-dimethylaminoacrylate to carry out a substitution reaction to generate intermediate I; 2) Add formylmethylhydrazine dropwise to react with intermediate I to undergo a hydroamination substitution reaction to generate intermediate II.
3. The method for efficiently synthesizing the key intermediate IV of Marbofloxacin according to claim 1, characterized in that: Intermediate II is hydrolyzed and deformylated under dilute sulfuric acid conditions, and the reaction time is 7 to 10 hours.
4. The method for efficiently synthesizing the key intermediate IV of Marbofloxacin according to claim 1, characterized in that: The molar ratio of intermediate III to methylpiperazine is 1.0:1.0-1.
1.
5. The method for efficiently synthesizing the key intermediate IV of Marbofloxacin according to claim 2, characterized in that: In the substitution reaction of step 1), the molar ratio of tetrafluorobenzoyl chloride, ethyl N,N-dimethylaminoacrylate and triethylamine is 1.0:1.0-1.3:1.0-1.
5.
6. The method for efficiently synthesizing the key intermediate IV of Marbofloxacin according to claim 2, characterized in that: In step 1), the dropping temperature is 35-40° C., the substitution reaction temperature is 80-90° C., and the reaction time is 2-4 h.
7. The method for efficiently synthesizing the key intermediate IV of Marbofloxacin according to claim 2, characterized in that: In step 2), the dropping temperature is 20-25° C., the reaction temperature is reflux, and the reaction time is 0.5-2 h.
8. The method for efficiently synthesizing the key intermediate IV of Marbofloxacin according to claim 2, characterized in that: The molar ratio of the intermediate I to formylmethylhydrazine is 1.0:1.0-1.
3.
9. The method for efficiently synthesizing the key intermediate IV of Marbofloxacin according to claim 2, characterized in that: The solvent is toluene.
10. A method for synthesizing intermediate II by one-pot two-step reaction, characterized in that: Tetrafluorobenzoyl chloride and ethyl N,N-dimethylaminoacrylate undergo substitution reaction under triethylamine conditions to generate intermediate I; intermediate I undergoes hydrogen amination substitution reaction with formylmethylhydrazine to generate intermediate II.